The basic hypothesis of this proposal is that Calcitonin Gene Related Peptide (CGRP) is an important mediator of vascular deregulation during the latter stages of septic shock. Moreover the effect of substances such as CGRP which rely, at least in part, on vascular smooth muscle cyclic adenosine monophosphate (cAMP) generation as a mechanism of action, show enhanced potency in the face of increased nitric oxide (NO) production due to a specific interaction between the vascular cGMP and cAMP systems. The studies described in this proposal are designed to; 1) further define the intracellular mechanisms of action of CGRP on vascular smooth muscle and, specifically, to define the interactions between CGRP and another mediator known to impact on vascular function during septic shock, NO and 2) to establish if a cause and effect relationship exists between augmented perivascular CGRP release during septic shock, and progressive vascular dysfunction.